Project Summary/Abstract Lewy Body dementias are a common form of degenerative dementia. These diseases are debilitating, causing visual hallucinations, fluctuations in consciousness, disturbed sleep, falls, and depression, all leading to loss of independence, disability and significant caregiver burden. In these disorders, the protein alpha-synuclein accumulates into pathognomonic ?Lewy bodies? and ?Lewy neurites?. Patients with Lewy Body dementia have diffuse intracellular cortical Lewy Bodies, cortical thinning, and loss of neuronal anatomy, including dendrites and spines. These changes may occur due to altered calcium regulation caused by alpha-synuclein oligomers, which accumulate under pathologic conditions. Overexpression of alpha-synuclein in humans leads to familial disease, including dementia, and therefore provides a useful model to evaluate the mechanisms of neuronal dysfunction. This proposal uses viral overexpression of alpha-synuclein in the cortex of mice to examine the pathological changes occurring in cortical neurons as the protein accumulates. Specifically, this proposal first tests the hypothesis that local alpha-synuclein accumulation induces dendritic spine instability, leading to dendritic spine loss overtime. This is tested using longitudinal, live animal, 2-photon imaging to repeatedly observe individual dendritic spines as pathology develops. Secondly, this proposal evaluates if calcium dynamics change over time due to alpha-synuclein accumulation, a potential mechanism for network dysfunction and anatomical pathology. The findings from this proposal will demonstrate how a-synuclein exerts its pathological effect in cortical cells and evaluate a mechanistic model based on Ca2+ dynamics. By including evaluation over time, these studies are more likely to model aspects of human disease and lead to translatable treatments. As a career development grant this proposal is ideal; it leverages the applicant?s past skills in 2- photon imaging of dendritic spines with a complementary, mechanistic and computational approach using Ca2+ imaging, which is novel to the applicant. The institution is dedicated to providing the support and resources necessary for the applicant?s success. There is strong mentorship available in areas of research proposed, supplemented with instruction by consultants and formal workshops. Together, this will provide key training opportunities that will advance the applicant?s career as an academic physician-scientist focusing on understanding and treating Lewy Body Dementias.